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Hepatic glucose cycling, whereby glucose is taken up by the liver, partially metabolized, then recycled to glucose, makes a substantial contribution to the development of hyperglycemia in IDDM. This stimulation of glucose cycling appears to be associated with elevated rates of fatty acid oxidation. Whether hepatic glucose cycling also contributes to the development of hyperglycemia in NIDDM is unclear. Using a model of NIDDM, the Zucker diabetic fatty (ZDF) rat, we determined whether glucose cycling was enhanced. Hepatocytes from ZDF rats exhibited higher rates of glucose phosphorylation and glycolysis, but there was no increase in the rate of cycling between glucose and glucose-6-phosphate or between glycolytically derived pyruvate and glucose. Despite the increased rates of glycolysis, the production of CO2 in liver cells from ZDF rats was no different from rates measured in cells from control animals. Instead, there was a large increase in the accumulation of lactate and pyruvate in the ZDF liver cells. The addition of 2-bromopalmitate, an inhibitor of fatty acid oxidation that inhibited glucose cycling in hepatocytes from IDDM rats, had no effect on glucose cycling in cells from ZDF rats. We therefore conclude that, unlike in IDDM, hepatic glucose cycling does not contribute to the development of hyperglycemia in the NIDDM Zucker rat. [ABSTRACT FROM AUTHOR]

The article presents the views of several individuals on an application to conserve the junior synonym Maculinea for the Large Blue butterfly which include Martin Benka, J. W. Phillips, and D. J. Simcox. Benka supports the application as Maculinea has shown to be widely used compared with Phengaris. Phillips believes that suspending the use of Maculinea would be confusing. Simcox notes that he and his colleagues use Maculinea to refer to the Large Blue butterfly.

An asymptotic analysis of the grazing-incidence problem is made for the point where the traction-free boundary of an elastic solid intersects the front of the plane pulse propagating parallel to it. [ABSTRACT FROM AUTHOR]

We have used a random walk model of glycolysis and gluconeogenesis to investigate the bioenergetic implications of considering the cell cytoplasm to be a uniform well-mixed compartment. Radiotracer studies conducted on hepatocytes harvested from fasted rats and incubated with 40 mM glucose and 10 mM lactate demonstrated simultaneous glycolysis and gluconeogenesis, with net glycolysis. Tracer introduced as glycerol was incorporated both into glucose (via gluconeogenesis) and into pyruvate (via glycolysis). The data allow us to place a lower bound on the energetic cost of futile cycles involving adenosine triphosphate (ATP) hydrolysis in the early phosphorylation steps of glycolysis. Applying the Markov Chain model for glucose undergoing metabolism to pyruvate, the expected number of ATP molecules hydrolysed is not less than 15 ATP molecules per glucose molecule. The data suggest that, in hepatocytes under the circumstances of this experiment, either glycolysis is a net consumer of ATP, or glycolysis and gluconeogenesis are compartmentalized to a greater extent than is generally supposed. [Copyright &y& Elsevier]

Combining genetic inheritance information, for both molecular profiles and complex traits, is a promising strategy not only for detecting quantitative trait loci (QTLs) for complex traits but for understanding which genes, pathways, and biological processes are also under the influence of a given QTL. As a primary step in determining the feasibility of such an approach in humans, we present the largest survey to date, to our knowledge, of the heritability of gene-expression traits in segregating human populations. In particular, we measured expression for 23,499 genes in lymphoblastoid cell lines for members of 15 Centre d'Etude du Polymorphisme Humain (CEPH) families. Of the total set of genes, 2,340 were found to be expressed, of which 31% had significant heritability when a false-discovery rate of 0.05 was used. QTLs were detected for 33 genes on the basis of at least one P value <.000005. Of these, 13 genes possessed a QTL within 5 Mb of their physical location. Hierarchical clustering was performed on the basis of both Pearson correlation of gene expression and genetic correlation. Both reflected biologically relevant activity taking place in the lymphoblastoid cell lines, with greater coherency represented in Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathways than in Gene Ontology database pathways. However, more pathway coherence was observed in KEGG pathways when clustering was based on genetic correlation than when clustering was based on Pearson correlation. As more expression data in segregating populations are generated, viewing clusters or networks based on genetic correlation measures and shared QTLs will offer potentially novel insights into the relationship among genes that may underlie complex traits. [ABSTRACT FROM AUTHOR]

P-selectin, a cell adhesion protein participating in the early stages of inflammation, contains multiple sorting signals that regulate its cell surface expression. Targeting to secretory granules regulates delivery of P-selectin to the cell surface. Internalization followed by sorting from early to late endosomes mediates rapid removal of P-selectin from the surface. We show here that the P-selectin cytoplasmic domain bound AP-2 and AP-3 adaptor complexes in vitro. The amino acid substitution L768A, which abolishes endosomal sorting and impairs granule targeting of P-selectin, reduced binding of AP-3 adaptors but not AP-2 adaptors. Turnover of P-selectin was 2.4-fold faster than turnover of transferrin receptor in AP-3-deficient mocha fibroblasts, similar to turnover of these two proteins in AP-3-competent cells, demonstrating that AP-3 function is not required for endosomal sorting. However, sorting P-selectin to secretory granules was defective in endothelial cells from AP-3-deficient pearl mice, demonstrating a role for AP-3 adaptors in granule assembly in endothelial cells. P-selectin sorting to platelet alpha-granules was normal in pearl mice, consistent with earlier evidence that granule targeting of P-selectin is mechanistically distinct in endothelial cells and platelets. These observations establish that AP-3 adaptor functions in assembly of conventional secretory granules, in addition to lysosomes and the 'lysosome-like' secretory granules of platelets and melanocytes.

A method for the preparation of intact rat hepatocytes in high yield was first described in 1969. The procedure involved digestion of hepatic tissue by perfusion of the liver with crude collagenase; later, purified collagenase without other enzymic additions was shown to be ineffective. Recently it has been discovered that the combination of purified collagenase plus elastase is superior to crude collagenase in that it consistently provides high yields of undamaged hepatocytes. The isolated hepatocyte preparation has proved particularly useful for the study of mechanisms responsible for long-range interactions within the cell. These can be studied over prolonged time courses and in the presence of graded concentrations of specific inhibitors. Studies of this kind have demonstrated a close relationship between cytoplasmic metabolic flows and mitochondrial forces and have also revealed that the cytoplasmic and mitochondrial free NAD-linked redox potentials are maintained by energy-dependent reactions.

This article explores differences in Social Security eligibility and benefit levels for older men and women using survey data from the Health and Retirement Study combined with administrative records on actual work histories and Social Security rules. We are able to determine the fully insured status of those persons, how close they are to meeting eligibility criteria when they are not fully insured, and their prospects for benefits. Around three-quarters of older women nearing retirement today will be fully insured for Social Security old-age benefits on the basis of their own accounts, but the rest would need substantial extra employment to rise above the eligibility threshold. Further, two-thirds of older married women who are fully insured have sufficient lifetime earnings to translate into an age-65 primary insurance amount worth at least half their husband's, but the other one-third can expect no additional retirement benefit from contributing to Social Security late in life. Finally, most wives will not be able to improve their benefits by working more under current rules. These results have mixed implications regarding the potential impact of women's rising labor force attachment on eventual retirement benefits. Working more years could increase women's chances of becoming eligible for Social Security benefits, but that effect is likely to be small. Furthermore, even when women do become fully insured according to the rules, not many wives will receive a higher benefit at the margin. The reason is that married women still receive higher Social Security benefits as a spouse than they do on the basis of their own work record. In fact, the net benefit from Social Security due to additional work is negative once one takes into account the Social Security contributions the women paid while employed. Benefits paid to widows are even more likely to be based on the spouse's work history rather than on the woman's. Hence, the rising labor market attachment of women in the future may increase their eligibility for benefits but will produce only modest (and often negative) impacts on their old-age Social Security benefits under current rules.

The stimulation of glucose phosphorylation in isolated hepatocytes by low fructose concentrations is transient due to the rapid metabolism of fructose. To prolong this stimulatory effect fructose was enzymically generated in the incubation medium from either sucrose with invertase or inulin with inulinase. A maximal rate of glucose phosphorylation was achieved when fructose was formed at at least 0.01 micromol/min, which maintained a concentration of 70 microM fructose in the medium. In the presence of a fructose concentration of 70 microM, the rate of phosphorylation with 5 mM glucose was doubled and remained constant over a 2.5 h period. Under these conditions the rate of glycolysis was increased more than 3-fold. The stimulation of flux through glucokinase by low concentrations of fructose decreased the proportion of glucose phosphorylated, which was cycled between glucose and glucose 6-phosphate, and increased the proportion that was glycolysed. The method described for maintaining the stimulation of glucose phosphorylation by isolated hepatocytes over prolonged incubation periods is especially suited to the further study of the control of glucokinase activity, in particular how the variation of flux through glucokinase affects the flux through all the pathways that utilize the product, glucose 6-phosphate.

To investigate the role of DNA strand breakage as the molecular lesion responsible for initiating genomic instability, five different strand-breaking agents, bleomycin, neocarzinostatin, hydrogen peroxide, restriction endonucleases, and ionizing radiation, were examined for their capacity to induce delayed chromosomal instability. These studies used GM10115 human-hamster hybrid cells, which contain one copy of human chromosome 4 in a background of 20-24 hamster chromosomes. Chromosomal instability was investigated using fluorescence in situ hybridization to visualize chromosomal rearrangements involving the human chromosome. Rearrangements are detected multiple generations after treatment, in clonal populations derived from single progenitor cells surviving treatment of the specified DNA-damaging agents. Clastogenic and cytotoxic activities of all agents were tested by examining chromosome aberration yields in first-division metaphases and by clonogenic survival assays. Analysis of over 250 individual clones representing over 50,000 metaphases demonstrates that when compared at comparable levels of cell kill, ionizing radiation, bleomycin, and neocarzinostatin are equally effective at eliciting delayed genomic instability. These observations document, for the first time, the persistent destabilization of chromosomes following chemical treatment. In contrast, the analysis of nearly 300 clones and 60,000 metaphases, involving treatment with four different restriction endonucleases and/or hydrogen peroxide, did not show any delayed chromosomal instability. These data indicate that DNA strand breakage per se does not necessarily lead to chromosomal instability but that the complexity or quality of DNA strand breaks are important in initiating this phenotype.

We describe a new approach to imaging neural current sources from measurements of the magnetoencephalogram (MEG) associated with sensory, motor, or cognitive brain activation. Many previous approaches to this problem have concentrated on the use of weighted minimum norm (WMN) inverse methods. While these methods ensure a unique solution, they do not introduce information specific to the MEG inverse problem, often producing overly smoothed solutions and exhibiting severe sensitivity to noise. We describe a Bayesian formulation of the inverse problem in which a Gibbs prior is constructed to reflect the sparse focal nature of neural current sources associated with evoked response data. We demonstrate the method with simulated and experimental phantom data, comparing its performance with several WMN methods.